2. Academic Validation
  3. Development of LM-41 and AF-2112, two flufenamic acid-derived TEAD inhibitors obtained through the replacement of the trifluoromethyl group by aryl rings

Development of LM-41 and AF-2112, two flufenamic acid-derived TEAD inhibitors obtained through the replacement of the trifluoromethyl group by aryl rings

  • Bioorg Med Chem Lett. 2023 Oct 15:95:129488. doi: 10.1016/j.bmcl.2023.129488.
Ahmed Fnaiche 1,  Léa Mélin 1,  Narjara González Suárez 1,  Alexis Paquin 1,  Victoria Vu 2,  Fengling Li 2,  Abdellah Allali-Hassani 2,  Albina Bolotokova 2,  Frédéric Allemand 3,  Muriel Gelin 3,  Philippe Cotelle 4,  Simon Woo 5,  Steven R LaPlante 5,  Dalia Barsyte-Lovejoy 2,  Vijayaratnam Santhakumar 2,  Masoud Vedadi 6,  Jean-François Guichou 7,  Borhane Annabi 8,  Alexandre Gagnon 9
Affiliations

Affiliations

  • 1 Département de chimie, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec H3C 3P8, Canada.
  • 2 Structural Genomics Consortium, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
  • 3 Centre de Biologie Structurale, CNRS, INSERM, Univ. Montpellier, Montpellier, France.
  • 4 Université de Lille, CHU Lille, INSERM-UMR-S-1172-JPArc-Centre de Recherche Jean-Pierre Aubert, Neurosciences et Cancer, F-59000 Lille, France.
  • 5 INRS-Centre Armand Frappier Santé Biotechnologie, Université du Québec, 531 Boulevard des Prairies, Laval, Québec H7V 1B7, Canada.
  • 6 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 7 Centre de Biologie Structurale, CNRS, INSERM, Univ. Montpellier, Montpellier, France. Electronic address: gagnon.alexandre@uqam.ca.
  • 8 Département de chimie, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec H3C 3P8, Canada. Electronic address: annabi.borhane@uqam.ca.
  • 9 Département de chimie, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec H3C 3P8, Canada. Electronic address: gagnon.alexandre@uqam.ca.
PMID: 37770003 DOI: 10.1016/j.bmcl.2023.129488
Abstract

The Hippo pathway regulates organ size and tissue homeostasis by controlling cell proliferation and Apoptosis. The YAP-TEAD transcription factor, the downstream effector of the Hippo pathway, regulates the expression of genes such as CTGF, Cyr61, Axl and NF2. Aberrant Hippo activity has been identified in multiple types of cancers. Flufenamic acid (FA) was reported to bind in a liphophilic TEAD palmitic acid (PA) pocket, leading to reduction of the expression of Axl and NF2. Here, we show that the replacement of the trifluoromethyl moiety in FA by aromatic groups, directly connected to the scaffold or separated by a linker, leads to compounds with better affinity to TEAD. Co-crystallization studies show that these compounds bind similarly to FA, but deeper within the PA pocket. Our studies identified LM-41 and AF-2112 as two TEAD Binders that strongly reduce the expression of CTGF, Cyr61, Axl and NF2. LM-41 gave the strongest reduction of migration of human MDA-MB-231 breast Cancer cells.

Keywords

Flufenamic acid; Hippo pathway; Niflumic acid; Transcription factors; YAP–TEAD.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155309
    99.82%, TEAD Inhibitor
    YAP
  • HY-155310
    TEAD Inhibitor
    YAP